The present invention relates to a class of substituted 1H-pyridinyl-2-one derivatives and to their use in therapy. More particularly, this invention is concerned with substituted 1H-pyridinyl-2-one derivatives which are ligands for GABAA receptors and are therefore useful in the therapy of deleterious mental states.
Receptors for the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are divided into two main classes: (1) GABAA receptors, which are members of the ligand-gated ion channel superfamily; and (2) GABAB receptors, which may be members of the G-protein linked receptor superfamily. Since the first cDNAs encoding individual GABAA receptor subunits were cloned the number of known members of the mammalian family has grown to thirteen (six xcex1 subunits, three xcex2 subunits, three xcex3 subunits and one xcex4 subunit). It may be that further subunits remain to be discovered; however, none has been reported since 1993.
Although knowledge of the diversity of the GABAA receptor gene family represents a huge step forward in our understanding of this ligand-gated ion channel, insight into the extent of subtype diversity is still at an early stage. It has been indicated that an a subunit, a xcex2 subunit and a xcex3 subunit constitute the minimum requirement for forming a fully functional GABAA receptor expressed by transiently transfecting cDNAs into cells. As indicated above, a xcex4 subunit also exists, but is present only to a minor extent in GABAA receptor populations.
Studies of receptor size and visualisation by electron microscopy conclude that, like other members of the ligand-gated ion channel family, the native GABAA receptor-exists in pentameric form. The selection of at least one xcex1, one xcex2 and one xcex3 subunit from a repertoire of thirteen allows for the possible existence of more than 10,000 pentameric subunit combinations. Moreover, this calculation overlooks the additional permutations that would be possible if the arrangement of subunits around the ion channel had no constraints (i.e. there could be 120 possible variants for a receptor composed of five different subunits).
Receptor subtype assemblies which do exist include, amongst many others, xcex11xcex22xcex32, xcex12xcex22/3xcex32, xcex13xcex2xcex32/3, xcex12xcex2xcex31, xcex15xcex23xcex32/3, xcex16xcex2xcex32, xcex16xcex2xcex4 and xcex14xcex2xcex4. Subtype assemblies containing an xcex11 subunit are present in most areas of the brain and are thought to account for over 40% of GABAA receptors in the rat. Subtype assemblies containing xcex12 and xcex13 subunits respectively are thought to account for about 25% and 17% of GABAA receptors in the rat. Subtype assemblies containing an xcex15 subunit are expressed predominantly in the hippocampus and cortex and are thought to represent about 4% of GABAA receptors in the rat.
A characteristic property of all known GABAA receptors is the presence of a number of modulatory sites, one of which is the benzodiazepine (BZ) binding site. The BZ binding site is the most explored of the GABAA receptor modulatory sites, and is the site through which anxiolytic drugs such as diazepam and temazepam exert their effect. Before the cloning of the GABAA receptor gene family, the benzodiazepine binding site was historically subdivided into two subtypes, BZ1 and BZ2, on the basis of radioligand binding studies. The BZ1 subtype has been shown to be pharmacologically equivalent to a GABAA receptor comprising the xcex11 subunit in combination with a xcex2 subunit and xcex32. This is the most abundant GABAA receptor subtype, and is believed to represent almost half of all GABAA receptors in the brain.
Two other major populations are the xcex12xcex2xcex32 and xcex13xcex2xcex32/3 subtypes. Together these constitute approximately a further 35% of the total GABAA receptor repertoire. Pharmacologically this combination appears to be equivalent to the BZ2 subtype as defined previously by radioligand binding, although the BZ2 subtype may also include certain xcex15-containing subtype assemblies. The physiological role of these subtypes has hitherto been unclear because no sufficiently selective agonists or antagonists were known.
It is now believed that agents acting as BZ agonists at xcex11xcex2xcex32, xcex12xcex2xcex32 or xcex13xcex2xcex32 subunits will possess desirable anxiolytic properties. The xcex11-selective GABAA receptor agonists alpidem and zolpidem are clinically prescribed as hypnotic agents, suggesting that at least some of the sedation associated with known anxiolytic drugs which act at the BZ1 binding site is mediated through GABAA receptors containing the xcex11 subunit. Accordingly, it is considered that GABAA receptor agonists which bind more effectively to the xcex12 and/or xcex13 subunit than to xcex11 will be effective in the treatment of anxiety with a reduced propensity to cause sedation. Also, agents which are antagonists or inverse agonists at xcex11 might be employed to reverse sedation or hypnosis caused by xcex11 agonists.
Compounds according to Formula (I) or a salt thereof are selective ligands for GABAA receptors useful for treatment of disorders of the central nervous system: 
The compounds of the present invention, being selective ligands for GABAA receptors, are therefore of use in the treatment and/or prevention of a variety of disorders of the central nervous system. Such disorders include anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, animal and other phobias including social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder; neuroses; convulsions; migraine; and depressive or bipolar disorders, for example single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorders, and cyclothymic disorder.
The present invention provides a compound which is a derivative of formula I or a salt or prodrug thereof: 
wherein:
R is hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy or C2-6 alkynyloxy, and when R is not hydrogen, R is optionally independently substituted by one or more halogen atoms or hydroxy, cyano or amino groups;
V is CH or N;
W is O or S;
X is phenyl unsubstituted or substituted with one or more groups independently selected from C1-6 alkyl, CF3, cyano, nitro, halogen, amino, C1-6 alkoxy, C1-6 alkylcarbonyloxy or C1-6 alkylcarbonylamino; a six-membered heteroaromatic group containing one or two nitrogen atoms or a five-membered heteroaromatic group containing one, two, three or four heteroatoms independently selected from N, O and S providing that not more than one heteroatom is selected from O and S, the heteroaromatic group being unsubstituted or substituted with one or more groups independently selected from halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C4-6 cycloalkenyl and CF3;
Y is hydrogen, NR1R2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Ar, O(CH2)nAr1, (CH2)jAr2, CkH2k-2Ar2, CkH2k-4Ar2 or NH(CH2)1Ar5;
R1 and R2 are independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 hydroxyalkyl and (CH2)mAr3;
Ar is thienyl, furyl or a six-membered heteroaromatic ring containing one or two nitrogen atoms which is unsubstituted or substituted with one or more groups independently selected from halogen and C1-6 alkyl groups and which is optionally fused to a benzene ring; or naphthyl or phenyl rings which rings are unsubstituted or substituted with one or more groups independently selected from halogen, cyano, amino, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CF3, CF3O, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C2-6 alkenylthio, C2-6 alkynylthio, hydroxy, hydroxyC1-6alkyl, NR3R4, OC(O)NR3R4, C1-6 alkoxyphenylC1-6alkoxy, cyanoC1-6alkyl, cyanoC2-6alkenyl, cyanoC2-6alkynyl, pyridyl, phenyl, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonylC1-6alkyl, C1-6 alkoxycarbonylC2-6alkenyl, C1-6 alkoxycarbonylC2-6alkynyl and xe2x80x94O(CH2)pOxe2x80x94 and which is optionally fused to a benzene ring;
Ar1, Ar2, Ar3 and Ar5 are independently selected from pyridyl; and phenyl which is unsubstituted or substituted with one or more groups independently selected from halogen, cyano, amino, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CF3, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C2-6 alkenylthio, C2-6 alkynylthio and xe2x80x94O(CH2)pOxe2x80x94;
Z is halogen, C3-6 cycloalkyl, C1-6 alkylthio, C2-6 alkenylthio, C2-6 alkynylthio, NR5R6, Ar4 or Het1;
R3, R4, R5 and R6 are independently as defined for R1 and R2;
Ar4 is phenyl which is unsubstituted or substituted with one or more groups independently selected from halogen, cyano, amino, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CF3, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C2-6 alkenylthio, C2-6 alkynylthio and xe2x80x94O(CH2)pOxe2x80x94;
Het1 is a four- or five-membered saturated ring containing a nitrogen atom optionally substituted by a hydroxy group; a six membered saturated ring containing a nitrogen atom, and optionally a further nitrogen atom or an oxygen atom; an unsaturated five-membered heterocyclic group containing one, two, three or four heteroatoms independently selected from N, O and S providing that not more than one heteroatom is selected from O and S; or an unsaturated six-membered heterocyclic group containing one or two nitrogen atoms; each of which moieties is unsubstituted or substituted by one or more groups independently selected from halogen, cyano, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CF3, C1-6 alkoxy, C2-6 alkenyloxy and C2-6 alkynyloxy;
j is 1, 2, 3 or 4;
k is 2, 3 or 4;
l is 1, 2, 3 or 4;
m and n are independently 0, 1, 2, 3 or 4; and
p is 1, 2 or 3.
R is preferably hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C2-6 alkenyloxy or C2-6 alkynyloxy, in particular hydrogen, C1-4 alkyl or C2-4 alkenyl. When R is not hydrogen, R may be unsubstituted or substituted by one or two, preferably one, substituent independently selected from halogen, preferably fluorine or chlorine, especially fluorine, and hydroxy. In particular R can be hydrogen, methyl, n-propyl, ethenyl, prop-1-en-3-yl, hydroxyethyl or fluoroethyl.
V is generally CH. V may be N.
W is generally O. W may be S.
When X is phenyl it is preferably unsubstituted or substituted with C1-6 alkyl, CF3, cyano, nitro, halogen, amino, C1-6 alkoxy, C1-6 alkylcarbonyloxy or C1-6 alkylcarbonylamino, for example, C1-6 alkyl, amino, halogen or C1-6 alkylcarbonylamino, more preferably unsubstituted or substituted with C1-6 alkylcarbonylamino and most preferably unsubstituted or substituted with methylcarbonylamino.
When X is phenyl it may be unsubstituted. When X is phenyl it may be unsubstituted or substituted by fluorine, amino or methylcarbonylamino.
When X is a heteroaromatic group it is preferably unsubstituted or substituted with halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C4-6 cycloalkenyl or CF3, more preferably unsubstituted or substituted with C1-6 alkyl or C3-6 cydoalkyl, most preferably unsubstituted or substituted with methyl or cyclopropyl. When X is a heteroaromatic group it may be unsubstituted or substituted by methyl, isopropyl, cyclopropyl, ethyl or chlorine.
When X is a heteroaromatic group it is preferably pyridyl or five-membered, in particular, an isothiazole, thiazole, pyrazolyl, thiadiazole oxadiazole, pyridine or thiophene, most preferably an isothiazol-5-yl group optionally substituted at the 3-position, a thiazol-2-yl group optionally substituted at the 4-position, a pyrazol-3-yl group optionally substituted at the 1-position, a thiadiazol-3-yl group, in particular 1,2,4-thiadiazol-3-yl group, optionally substituted at the 5-position, an oxadiazol-3-yl group, in particular a 1,2,4-oxadiazol-3-yl group, optionally substituted at the 5-position, a pyridin-2-yl group, a thien-2-yl group optionally substituted at the 4-position, a thien-3-yl group.
Y is preferably hydrogen, NR1R2, C2-6 alkynyl, Ar, O(CH2)nAr1 or CkH2k-4A2.
R1 and R2 are preferably independently selected from C1-6 alkyl and (CH2)mAr3 and most preferably from methyl and (CH2)mAr3.
When Ar is thienyl or furyl, thienyl is preferred, it is preferably unsubstituted or substituted with halogen or C1-6 alkyl and optionally fused to a benzene ring and most preferably unsubstituted or fused to a benzene ring.
When Ar is a six-membered heteroaromatic ring it is preferably pyridyl or pyrimidinyl, and it is unsubstituted or substituted with halogen or C1-6 alkyl and most preferably unsubstituted.
When Ar is naphthyl it is preferably unsubstituted and when phenyl it is preferably unsubstituted or substituted with Rx and/or Ry and/or Rz wherein Rx and Ry are independently chosen from halogen, cyano, amino, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CF3, OCF3, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C2-6 alkenylthio, C2-6 alkynylthio, hydroxy, hydroxyC1-6alkyl, NR3R4, OC(O)NR3R4, C1-6 alkoxyphenylC1-6alkoxy, cyanoC1-6alkyl, cyanoC2-6 alkenyl, cyanoC2-6 alkynyl, pyridyl, phenyl, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonylC1-6alkyl, C1-6 alkoxycarbonylC2-6alkenyl, C1-6 alkoxycarbonylC2-6alkynyl and xe2x80x94O(CH2)pOxe2x80x94 and Rz is halogen, C1-6 alkyl or C1-6 alkoxy and Ar is optionally fused to a benzene ring. More preferably, Rx and Ry are independently chosen from halogen, C1-6 alkoxy, xe2x80x94O(CH2)pOxe2x80x94, hydroxyC1-6alkyl, C1-6 alkylthio, C1-6 alkoxyphenylC1-6alkoxy, NR3R4, OC(O)NR3R4, cyanoC2-6alkenyl, pyridyl, C1-6 alkoxycarbonyl, C1-6 alkoxycarbonylC2-6 alkenyl, phenyl and OCF3. Most preferably, when Ar is phenyl, it is unsubstituted and optionally fused to a benzene ring or substituted with one, two or three groups independently chosen from fluorine, chlorine, bromine, methoxy and methyl, or with xe2x80x94O(CH2)pOxe2x80x94, hydroxymethyl, ethoxy, isopropoxy, methoxyphenylmethoxy, NR3R4, O(CO)NR3R4, cyanoethenyl, pyridyl, ethoxycarbonyl, ethoxycarbonylethenyl, methylthio, phenyl, ethyl or CF3O.
Ar1, Ar2, Ar3 and Ar5 are independently preferably pyridyl; or phenyl which is unsubstituted or substituted with halogen, cyano, amino, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CF3, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C2-6 alkenylthio, C2-6 alkynylthio or xe2x80x94O(CH2)pOxe2x80x94. More preferably when any of Ar1, Ar2, Ar3 and Ar5 are phenyl the one that is phenyl is unsubstituted or substituted with methyl.
Ar4 is preferably phenyl which is unsubstituted or substituted with halogen, cyano, amino, nitro, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CF3, C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, C1-6 alkylthio, C2-6 alkenylthio, C2-6 alkynylthio or xe2x80x94O(CH2)pOxe2x80x94 and most preferably unsubstituted phenyl.
Z is preferably chloro, C3-6 cycloalkyl, C1-6 alkylthio, NR5R6, Ar4 or Het1 and most preferably chloro, C3-5 cycloalkyl, methylthio, NR5R6, Ar4 or Het1. When Het1 is a saturated ring it is preferably unsubstituted or substituted with halogen, cyano, amino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CF3, C1-6 alkoxy, C2-6 alkenyloxy or C2-6 alkynyloxy; more preferably it is a derivative of piperidine, thiomorpholine, azetidine, pyrrolidine or morpholine which derivative is preferably unsubstituted and which is preferably attached to the rest of the molecule via a nitrogen ring atom. When Het1 is a derivative of pyrrolidine it may be unsubstituted or substituted by a hydroxy group.
When Het1 is an unsaturated group it is preferably unsubstituted or substituted with halogen, cyano, amino, Chd 1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, CF3, C1-6 alkoxy, C2-6 alkenyloxy or C2-6 alkynyloxy, more preferably it is unsubstituted or substituted with C1-6 alkyl and most preferably it is unsubstituted or substituted with methyl. Preferably when Het1 is an unsaturated group it is a derivative of furan, thiophene, imidazole, pyridine, pyrazine, pyrimidine or pyridazine. When Heti is furan it is preferably unsubstituted or substituted with C1-6 alkyl, more preferably it is unsubstituted or substituted with methyl. When Het1 is an unsaturated group it may be unsubstituted.
R3 and R4 are preferably independently C1-6 alkyl and most preferably are both methyl.
R5 and are preferably independently chosen from hydrogen and C2-6 alkynyl, more preferably from hydrogen and propenyl and most preferably one is hydrogen and the other is propenyl.
j is preferably 1 or 2.
k is preferably 2.
l is preferably 1.
m and n are preferably 1.
p is preferably 1 or 2 and most preferably 2.
As used herein, the expression xe2x80x9cC1-6 alkylxe2x80x9d includes methyl and ethyl groups, and straight-chained or branched propyl, butyl, pentyl and hexyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as xe2x80x9cC1-6 alkoxyxe2x80x9d and xe2x80x9cC1-4 alkylxe2x80x9d are to be construed accordingly.
The expression xe2x80x9cC2-6 alkenylxe2x80x9d includes ethenyl and straight-chained or branched propenyl, butenyl, pentenyl and hexenyl groups. Particular alkenyl groups are ethenyl, n-propenyl, isopropenyl and butenyl. Derived expressions such as xe2x80x9cC2-4 alkenylxe2x80x9d and xe2x80x9cC1-6 alkenyloxyxe2x80x9d are to be construed accordingly.
The expression xe2x80x9cC2-6 alkynylxe2x80x9d includes ethynyl and propynyl groups and straight-chained or branched butynyl, pentynyl and hexynyl groups. Particular alkynyl groups are ethynyl, propynyl, butynyl and isobutynyl. Derived expressions such as xe2x80x9cC1-6 alkynyloxyxe2x80x9d are to be construed accordingly.
Typical C3-6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Derived expressions such as xe2x80x9cC3-5 cycloalkylxe2x80x9d are to be construed in an analogous manner.
The expressions xe2x80x9cfive-membered heteroaromatic groupxe2x80x9d and xe2x80x9cunsaturated five-membered heterocyclic groupxe2x80x9d as used herein include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl and thiadiazolyl groups.
The expression xe2x80x9csix-membered heteroaromatic ringxe2x80x9d as used herein includes pyridyl, pyrazinyl, pyrimidinyl and pyridazinyl groups.
The expression xe2x80x9cunsaturated six-membered heterocyclic groupxe2x80x9d as used herein includes pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl groups.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in uiuo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
Where the compounds according to the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds according to the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.
The compounds of the present invention possess desirable binding properties at various GABAA receptor subtypes. The compounds in accordance with the present invention have good affinity as ligands for the xcex12 and/or xcex13 subunit of the human GABAA receptor. Typically, the compounds of this invention display more effective binding to the xcex12 and/or xcex13 subunit than to the xcex11 subunit. Typically, the compounds of the present invention have a binding affinity (Ki) for the subunit of 100 nM or less.
Specific compounds within the scope of the invention include:
3-(4-methoxyphenyl)-1-methyl-5-(thiazol-2-yl)-1H-[2,4xe2x80x2]bipyridinyl-6-one;
5-(4-methoxyphenyl)-1-methyl-6-(5-methylfuran-2-yl)-3-(3-methyl-[1,2,4]oxadiazol-5-yl)-1H-pyridin-2-one;
3-(4-methoxyphenyl)-1-methyl-5-(4-methylthiazol-2-yl)-1H-[2,4xe2x80x2]bipyridinyl-6-one;
5-(4-methoxyphenyl)-1-methyl-3-(thiazol-2-yl)-6-(3-thienyl)-1H-pyridin-2-one;
5-(4-methoxyphenyl)-1-methyl-3-(5-cyclopropyl-[1,2,4]oxadiazol-3-yl)-6-(3-thienyl)-1H-pyridin-2-one;
5-(4-methoxyphenyl)-1-methyl-6-(5-methylfuran-2-yl)-3-(thiazol-2-yl)-1H-pyridin-2-one;
3-(4-methoxyphenyl)-1-methyl-5-(thiophen-2-yl)-1H-[2,4xe2x80x2]bipyridinyl-6-one;
3-(4-methoxyphenyl)-1-methyl-5-(4-cyclopropylthiazol-2-yl)-1H-[2,4xe2x80x2]bipyridinyl-6-one;
1-methyl-3-(4-pyridyl)-5-(thiazol-2-yl)-1H-[2,4xe2x80x2]bipyridinyl-6-one;
3-(4-methoxyphenyl)-1-methyl-5-(4-methylthiophen-2-yl)-1H-[2,4xe2x80x2]bipyridinyl-6-one;
5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-pyridazin-4-yl-1H-pyridin-2-one;
1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridazin-4-yl)-5-(2,4,6-trifluorophenyl)-1H-pyridin-2-one;
5-benzyloxy-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridin-4-yl)-1H-pyridin-2-one;
5-benzyloxy-1 -methyl-3-(4-methylthiazol-2-yl)-6-phenyl-1H-pyridin-2-one;
1-methyl-3-(1-methylpyrazol-3-yl)-5-(4-methoxyphenyl)-6-(pyridin-4-yl)-1H-pyridin-2-one;
5,6-diphenyl-1-methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one; 5-(3,4methylenedioxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyridin-4-yl)-1H-pyridin-2-one;
5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(pyrazin-2-yl)-1H-pyridin-2-one;
5-(4-methoxyphenyl)-6-(4-pyridyl)-3-phenyl-1-methyl-1H-pyridin-2-one;
5-(4-methoxyphenyl)-3-(3-methylisothiazol-5-yl)-6-(4-pyridyl)-1-methyl-1H-pyridin-2-one;
1-methyl-3-(4-methylthiazol-2-yl)-5-(N-methyl-N-benzylamino)-6-(4-pyridyl)-1H-pyridin-2-one;
1-methyl-3,5-diphenyl-6-(4-pyridyl)-1H-pyrazin-2-one;
5-(4-methoxyphenyl)-1-methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-pyridin-2-one;
6-dimethylamino-5-(4-Methoxyphenyl)-1 -methyl-3-(4-methylthiazol-2-yl)-1H-pyridin-2-one;
1-methyl-3-(4-methylthiazol-2-yl)-6-(4-morpholino)-1H-[3,4xe2x80x2]bipyridin-2-one;
1-methyl-3-(4-methylthiazol-2-yl)-6-(1-pyrrolidino)-1H-[3,4xe2x80x2]bipyridin-2-one;
and salts and prodrugs thereof.
The invention also provides pharmaceutical compositions comprising one or more compounds of this invention and a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Typical unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of anxiety, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
The present invention also provides a compound of formula I for use in a method of treatment of the human or animal body, in particular for use in the treatment of anxiety.
The present invention further provides the use of a compound of formula I for the manufacture of a medicament for the treatment of disorders for which the administration of a ligand for the GABAA receptor xcex12 and/or xcex13 subunits is required, for example, for the treatment of anxiety.
There is also disclosed a prophylactic or therapeutic method of treatment of a subject suffering from a condition for which the administration of a ligand for the GABAA receptor xcex12 andlor xcex13 subunit is required, which comprises administering to that subject a prophylactically or therapeutically effective amount of a compound of formula I. An example of such a condition is anxiety.
The present invention also provides a process for producing a compound of formula I in which V is CH which comprises:
(a) Reacting a compound of formula II with a compound of formula III 
xe2x80x83wherein Y is as defined above, G is Z, or when Z is a nucleophile, G optionally represents a leaving group such as methoxy, Rxe2x80x2 is a leaving group such as C1-6 alkyl, C2-6 alkenyl or C2-6 alkynyl which is unsubstituted or substituted with one or more halogen atoms and is typically C1-6 alkyl such as methyl or tertiary butyl and J is hydroxy or a halogen atom, preferably hydroxyl, to give a compound of formula IV: 
xe2x80x83wherein G, Rxe2x80x2 and Y are as defined above.
The compound of formula II is typically activated before reaction, for example, by reacting with N, N-carbonydiimidazole in a suitable solvent such as dry tetrahydrofuran. The compound of formula III is optionally converted into its enolate before reaction by reacting with a strong base such as lithium diisopropylamide in a suitable solvent such as dry tetrahydrofuran optionally with cooling, typically to xe2x88x9278xc2x0 C.
Activated compound II is typically reacted without purification as is the compound of formula III when activated.
When the compound of formula III is activated, reaction with the compound of formula II is typically carried out with cooling generally to xe2x88x9278xc2x0 C. When the compound of formula III is not activated it is typically reacted with the compound of formula II with cooling, generally to xe2x88x9230xc2x0 C., and with a strong base, such as sodium hydride; the reaction mixture is generally stirred for about one hour and then allowed to warm gradually to room temperature typically for about eight hours.
(b) Converting the compound of formula IV into a compound of formula V: 
xe2x80x83wherein G and Y are as defined above, which is achieved typically at room temperature or with heating, for example to 150xc2x0 C., for from 2 to 18 hours, in a solvent such as dimethyl sulfoxide, generally in the presence of a salt such as sodium chloride and water; or in the presence of an acid such as trifluoracetic acid.
Alternatively, a compound of formula (V) in which Y is NR1R2, G is Z and R1 and R2 are as defined above, can be obtained by reacting a compound of formula HNR1R2 with a compound of formula XIX: 
wherein Z is as defined above and L7 is a leaving group such as a halogen, e.g. bromine, typically in the form of the hydrohalide. The reaction is typically carried out in a solvent such as dichloromethane at about room temperature for about 18 hours.
(c) Reacting the compound of formula V with a compound of formula VI: 
xe2x80x83wherein Rxe2x80x3 and Rxe2x80x2xe2x80x3 are independently hydrogen or C1-6 alkyl, such as methyl, and L1 and L2 are leaving groups such as C1-6 alkoxy, typically methoxy, to give a compound of formula VII: 
xe2x80x83wherein G, Rxe2x80x3, Rxe2x80x2xe2x80x3 and Y are as defined above.
The reaction is typically carried out in a solvent such as dimethyl-formamide at room temperature or at an elevated temperature such as 80xc2x0 C. for from 3 to 20 hours.
(d) Reacting the compound of formula VII with a compound of formula VIII: 
xe2x80x83wherein X and R are as defined above, to give a compound of formula Ixe2x80x2: 
xe2x80x83wherein R, X and Y are as defined above and when G was Z, Gxe2x80x2 is Z and when G was a leaving group, Gxe2x80x2 is hydroxy, i.e. when Gxe2x80x2 is Z the compound of formula Ixe2x80x2 is a compound of formula I in which V is CH.
The reaction is typically carried out under an inert atmosphere, such as nitrogen, in the presence of a small quantity of a protic solvent such as methanol, with a strong base, such as sodium hydride, in a solvent such as tetrahydrofuran or dimethylformamide, at from room temperature to 50xc2x0 C. for from 15 to 20 hours.
(e) When G1 is OH, reacting with halogenating agent such as POCl3 to obtain a compound of formula Ixe2x80x3: 
xe2x80x83wherein R, X and Y are as defined above and Gxe2x80x3 is halogen, for example chlorine. This reaction is generally carried out under reflux under an inert atmosphere such as nitrogen for about one and a half hours.
(f) Reacting the compound of formula Ixe2x80x3 with a compound of formula Zxe2x80x94H, wherein Z is as defined above, generally in a solvent such as DMSO, typically at about 100xc2x0 C. for about 18 hours, to obtain a compound of formula I in which Z is a nucleophile and V is CH.
In an alternative process, a compound of formula I in which V is CH is produced by a process comprising:
(a) Reacting a compound of formula V with a compound of formula IX:
NHRxe2x80x83xe2x80x83(IX)
xe2x80x83to give a compound of formula X: 
xe2x80x83wherein R, Y and Z are as defined above.
The reaction is typically carried out in a solvent such as chloroform, under an inert atmosphere, such as nitrogen, with cooling, for example to 0xc2x0C., with a catalyst, such as titanium tetrachloride, for from 5 to 10 hours.
(b) Reacting the compound of formula X with a compound of formula XI: 
xe2x80x83wherein L4 is a leaving group such as chlorine and P is a protecting group such as benzyl, to give a compound of formula XII: 
xe2x80x83wherein P, L5, R, Y and Z are as defined above.
The reaction is typically carried out in a solvent, such as dry tetrahydrofuran, at a reduced temperature, such as xe2x88x9278xc2x0 C., under an inert atmosphere such as nitrogen followed by warming, typically to 0xc2x0 C., for from 1 to 3 hours.
(c) Reacting the compound of formula XII in a Vilsmeier reaction, typically using POCl3 and dimethylformamide, to give a compound of formula XIII: 
xe2x80x83wherein R, P, Y and Z are as defined above.
The reaction is generally carried out by adding POCl3 to the compound of formula XII at about room temperature and allowing the reaction to proceed for about an hour. DMF is then generally added, typically with cooling to about 0xc2x0 C. following by heating to about 75xc2x0 C. for about 90 minutes. This is typically followed by further cooling to about 0xc2x0 C. and the addition of further dimethylformamide followed by heating to about 75xc2x0 C. for about 3 hours.
(d) Deprotecting the compound of formula XIII to obtain a compound of formula XIV: 
xe2x80x83wherein R, Y and Z are as defined above, typically by reacting in a transfer dehydrogenation reaction, for example using palladium on carbon, in the presence of a hydrogen source such as ammonium formate, an acid such as glacial acetic acid and in a solvent such as methanol for about 3.5 hours at about room temperature.
(e) Converting the hydroxy group in the compound of formula XIV into a leaving group by reaction with an acid derivative of formula XV:
L6xe2x80x94Kxe2x80x83xe2x80x83(XV)
xe2x80x83wherein K is an acyl or sulfonyl group, such as SO2CF3, and L6 is a leaving group such as OSO2CF3, to give a compound of formula XVI: 
xe2x80x83wherein K, R, Y and Z are as defined above.
The reaction is generally carried out in a solvent such as dry dichloromethane in the presence of a base such as pyridine generally with cooling to about xe2x88x9278xc2x0 C. and for about one hour.
(f) Reacting the compound of formula XVI with a compound of XVII:
Xxe2x80x94B(OH)2xe2x80x83xe2x80x83(XVII)
xe2x80x83wherein X is as defined above, to obtain a compound of formula I. The reaction is carried out in the presence of a transition metal catalyst such as Pd(PPh3)4 generally under an inert atmosphere, such as nitrogen, typically at reflux, for about two hours.
Compounds of formula XVII can be made by reacting a compound of formula XVIII:
xe2x80x83Xxe2x80x94Hxe2x80x83xe2x80x83(XVIII)
wherein X is as defined above, with a trialkylborate, such as trimethylborate, in the presence of a strong base, such as n-butyllithium, generally at room temperature for about two hours.
Compounds of formula XVIII are commercially available or can be made by known methods.
Where they are not commercially available, the starting materials of formulae II, III, HNR1R2, XIX, VI, VIII, IX, Zxe2x80x94H, XI and XV may be prepared by standard methods well known from the art.
Compounds of formula I in which W is S can be prepared by reacting the analagous compound in which W is O with Lawesson""s reagent or P2S5.
Compounds of formula I in which V is N can be prepared by reacting a compound of formula: 
with Z-boronic acid (XX) wherein R, X, Y and Z are as previously defined. The compound of formula XX is generally in the form of a salt, such as the lithium salt. The reaction is generally carried out under an inert atmosphere such as nitrogen and in a solvent such as 3:1 ethylene glycol dimethylether:water. Generally addition of the compound of formula XX to the compound of formula XIX is followed by addition of a salt, such as sodium carbonate, and then a catalyst, such as tetrakistriphenylphosphine palladium. The order in which these compounds are combined is not critical. The reaction is generally carried out at reflux for several hours.
The compound of formula XIX can be prepared by reacting a compound of formula: 
with a compound of formula:
Lixe2x80x94Rxe2x80x83xe2x80x83(XXII)
wherein R, X and Y are as previously defined. The reaction is generally preceded by addition of a strong base, such as NaH, to the compound of formula XXI generally at 0xc2x0 C. under an inert atmosphere such as nitrogen in a solvent such as 4:1 ethylene glycol dimethylether:dimethylformamide for about 5 minutes. The reaction between the compounds of formulae XXI and XXII is then carried out for several hours.
Compounds of formula XXI can be prepared by methods analagous to that disclosed in Cheeseman et al., J. Chem. Soc. Chem. Commun. 1971, (18), 2977-2979 from known starting materials which are either commercially available or can be made by standard methods well known in the art.
Compounds of formula XX and XXII are either commercially available or can be made by standard techniques well known in the art.
Compounds of formula Ixe2x80x3 constitute a further feature of the present invention as they act as ligands of GABAA receptors containing the xcex12 and/or xcex13 subunits. Preferred substitution patterns of these compounds are the same as for the compounds of formula I mutatis mutandis.
It will be understood that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula I by techniques known from the art.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The novel compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The novel compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-1-tartaric acid, followed by fractional crystallization and regeneration of the free base. The novel compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.